Preparation of ethylenediaminetriacetic acid

ABSTRACT

Synthesis of ethylenediaminetriacetic acid (ED3A) or its salts is disclosed. A salt of N,N&#39;-ethylenediaminediacetic acid (ED2AH 2 ) is condensed with formaldehyde to form a stable 5-membered ring intermediate. The addition of cyanide across this cyclic material forms ethylenediamine N,N&#39;-diacetic acid-N&#39;-cyanomethyl or salts thereof (mononitrile-diacid). The nitrile in aqueous solutions may be spontaneously cyclized to form 2-oxo-1,4-piperazinediacetic acid (3KP) or salts thereof, which is the desired cyclic intermediate. In the presence of excess base, salts of ED3A are formed in excellent yield and purity. Alternatively, the starting material is ED2AH a  X b , where x is a base cation, e.g., an alkali or alkaline earth metal, a is 1 to 2, and b is 0 to 1 in aqueous solutions. The reaction mixture also can be acidified to ensure complete formation of carboxymethyl-2-oxopiperazine (the lactam) prior to the reaction. Formaldehyde is added, essentially resulting in the hydroxymethyl derivative. On the addition of a cyanide source, 1-cyanomethyl-4-carboxymethyl-2-ketopiperazine (mononitrile diacid) or a salt thereof is formed. Upon the addition of any suitable base or acid, this material may be hydrolyzed to 3KP. The addition of a base will open this ring structure to form the salt of ED3A.

This application is a divisional of application Ser. No. 07/806,567 filed Dec. 12, 1991, now U.S. Pat. No. 5,250,728.

BACKGROUND OF THE INVENTION

Ethylenediaminetriacetic acid (ED3A) or its salts (such as ED3ANa₃) has applications in the field of chelating chemistry, and may be used as a starting material in the preparation of strong chelating polymers, oil soluble chelants, surfactants and others. Conventional routes for the synthesis of ethylenediaminetriacetic acid were achieved via its N-benzyl derivative, which was subsequently hydrolyzed in alkaline solutions to ED3ANa₃, thus avoiding cyclization to its 2-oxo-1,4-piperazinediacetic acid (3KP) derivative. Syntheses attempted by both the alkaline condensation of chloroacetic acid with ethylenediamine, and the carboxymethylation of the diamine with formaldehyde and sodium cyanide resulted in complex mixtures requiring complex extraction techniques (e.g. almost exclusive solubility of 3KP in boiling dimethylformamide, Can. J. Chemistry 1970, 48(1), 163-175) to generate the desired product, and then in only relatively poor yield. In addition, conventional processes resulted in large quantities of by-product, such as ethylenediaminetetraacetic acid (ED4A). Where the by-products were especially objectionable, complicated blocking techniques were necessary in order to achieve a relatively pure solution.

One example of the synthesis of ethylenediamine-N,N,N'-triacetic acid is shown in Chemical Abstracts 78, Vol. 71, page 451, no. 18369c, 1969. There it is disclosed that ethylenediamine reacts with ClH₂ CCO₂ H in a 1:3 molar ratio in basic solution at 10° C. for 24 hours to form a mixture from which ethylenediamine-N,N,N'-triacetic acid can be separated by complexing the same with Co(III). The resulting cobalt complexes can be isolated through ion exchange.

It is therefore desirable to produce ethylenediaminetriacetic acid or its salts in high conversions and excellent yield.

SUMMARY OF THE INVENTION

The problems of the prior art have been overcome by the instant invention, which provides a simple process for the synthesis of ED3A or its salts. Specifically, a salt of N,N'-ethylenediaminediacetic acid (ED2AH₂) is condensed with formaldehyde to form a stable 5-membered ring intermediate. The addition of cyanide across this cyclic material forms ethylenediamine N,N'-diacetic acid-N'-cyanomethyl or salts thereof (mononitrile-diacid). The nitrile in aqueous solutions may be spontaneously cyclized to form 3KP or salts thereof, which is the desired cyclic intermediate. In the presence of excess base, salts of ED3A are formed in excellent yield and purity.

In an alternative embodiment, the starting material is ED2AH_(a) X_(b), where X is a base cation, e.g., an alkali or alkaline earth metal, a is 1 to 2, and b is 0 to 1 in aqueous solutions. The reaction mixture also can be acidified to ensure complete formation of carboxymethyl-2-oxopiperazine (the lactam) prior to the reaction. Formaldehyde is added, essentially resulting in the hydroxymethyl derivative. On the addition of a cyanide source, 1-cyanomethyl-4-carboxymethyl-3-ketopiperazine (mononitrile monoacid) or a salt thereof is formed. In place of CH₂ O and a cyanide source, HOCH₂ CN, which is the reaction product of formaldehyde and cyanide, may also be employed in this method. Upon the addition of any suitable base or acid, this material may be hydrolyzed to 3KP. The addition of a base will open this ring structure to form the salt of ED3A.

DETAILED DESCRIPTION OF THE INVENTION

Suitable salts of ethylenediaminediacetic acid useful as the starting material in the first embodiment of the instant invention include alkali and alkaline earth metal salts, in particular, the sodium and potassium salts. For purposes of illustration, the sodium salt will be used, although it should be understood that other salts may be employed without departing from the spirit and scope of the invention. Step 1 in the overall reaction scheme is the alkaline condensation of formaldehyde with N,N'-ethylenediamine disodium acetate to form a 5-membered ring structure, 1,3-bis(carboxymethyl)imidazolidine, and is illustrated as follows: ##STR1##

The above reaction may be carried out in the presence of additional base. Suitable bases include alkali and alkaline earth metal hydroxides, preferably sodium and potassium hydroxide. Compound (I) is the bridged reaction product of EDDANa.sub.(1.0→2.0) and formaldehyde, which the present inventor has found to be a stable intermediate in the ED3A synthesis. Compound (I) is formed easily between 0° and 110° C. The Step I reaction proceeds quickly and forms readily at pH's greater than about 7.0. Preferably the temperature employed is about 0° to 65° C., most preferably 15° to 65° C., although temperatures higher than 65° C. are operable. Formaldehyde can be used in stoichiometric amounts, although it is preferred that a slight molar excess be used, preferably 0.5 %-2.0%. Preferably the concentration of the formaldehyde is 55 % or less in aqueous solution. Paraformaldehyde also can be used.

The second step in the reaction scheme is illustrated below: ##STR2##

Compound (II) is readily formed at temperatures between 0° and 110° C. The reaction should be conducted at temperatures at or below the boiling point of the solution. Preferably the reaction is carried out at temperatures from about 0° to about 65° C., most preferably about 15° to 65° C. to enhance the reaction rate. Suitable sources of cyanide include gaseous hydrogen cyanide, an aqueous solution of hydrogen cyanide, or alkali metal cyanide such as sodium cyanide or potassium cyanide, etc. The cyanide may be used in stoichiometric amounts, although slight molar excesses may be used, preferably 0.5%-2.0%.

Step III in the reaction sequence is the hydrolysis of compound (II) to the monoamide-diacid compound (III) (partially hydrolyzed mononitrile diacid) and its spontaneous cyclization to 3KP. Compound (IV) forms readily in the presence of a base such as alkali metal or alkaline earth metal hydroxides. Preferably the base is NaOH. Mole ratios of <3.0M base: 1M ED2AH₂ but preferably <2.0 M base: 1M ED2AH₂ are employed. Higher concentrations of base (i.e. >3.0 M base: M ED2AH₂) cause some disproportionation of the diacid mononitrile and some ED4A (ethylenediaminetetraacetic acid) is formed, especially at temperatures >65° C. In particular, the concentration of ED4A is found to be in direct proportion to the amount of excess caustic employed, when high temperature reactions are conducted and high molar ratios of base are employed (>2.0M base: 1M ED2AH₂), which may be attributed to the simultaneous hydrolysis of 3KP and disproportionation of the mononitrile-diacid. When the mole ratio of base to ED2A is <2.0, higher temperatures may be used. Also, in Step III ammonia is eliminated between an amide group and an imino group on the same molecule. However, at lower temperatures (<65° C.) higher amounts of base may be employed (>2.0M) and hydrolysis of compound (II) can proceed directly to ED3A without cyclization. ##STR3##

Step IV is the hydrolysis of 3KPNa₂ by at least the addition of 1 equivalent of caustic, preferably a 1 molar excess of caustic. This amounts to approximately 5 % weight excess (free) caustic in solution on a 40% ED3ANa₃ solution. The solution is boiled under atmospheric pressure to the desired concentration. Preferably the reaction is carried out by raising the temperature from the temperature in Step III to the boil over a period from about 30 minutes to about 6 hours. ##STR4##

The resulting solutions typically give approximately 35-40% ED3ANa₃, with approximately 2% 3KPNa₂ remaining as an unopened ringed structure. This corresponds to about a 94% conversion to ED3ANa₃, with the remaining 6% of mass existing as 3KPNa₂. Acidification of this mass to pH's <6.0 to produce ED3AH₃ is not possible, as cyclization to 3KPH₂ will eventually occur.

The foregoing synthetic scheme results in conversions to ED3ANa₃ in excess of 90%, with the residual proportion being 3KPNa₂ to give a total mass balance of virtually 100%. The reactions are tolerant to a wide pH range.

In an alternative embodiment, the starting material is ED2AH_(a) X_(b), where x is a base, e.g., an alkali or alkaline earth metal, a is 1 to 2, and b is 0 to 1 in aqueous solutions. The reaction mixture also can be acidified with acids having pK_(a) 's less than or equal to 3, prior to during or after the addition of a cyanide source, to ensure complete formation of carboxymethyl-2-oxopiperazine (the lactam). Formaldehyde is added, essentially resulting in the hydroxymethyl derivative. Upon the addition of a cyanide source, 1-cyanomethyl-4-carboxymethyl-3-ketopiperazine or a salt thereof is formed, and can be isolated in good yield in crystalline form by conventional means after cooling the reaction mixture. Conversions are quantitative. Furthermore, in place of CH₂ O and a cyanide source, HOCH₂ CN, which is the reaction product of formaldehyde and cyanide, may also be employed in this method. Upon the addition of any suitable base or acid, this material may be hydrolyzed to 3KP. The addition of a base (>2.0 equivalents but preferably greater than or equal to 3.0 equivalents will open this ring structure to form the salt of ED3A. Heating the reaction mixture will enhance the rate of reaction.

The overall reaction scheme is shown below: ##STR5##

In a further embodiment, EDDA is allowed to form the lactam (carboxymethyl-2-oxo-piperazine) by acidification, and the lactam is reacted with chloro or bromo acetic acid to form ED3A or 3KP.

The following procedure to obtain ED2AH₂ was for experimental purposes only. Far less elaborate schemes for the production of ED2AH₂ are possible. Any schemes known in the art can be employed for the production of ED2AH₂ and its salts, and the instant invention is not to be limited by any particular scheme.

In the following examples, all batches were synthesized from EDDAH₂ (98.20%) obtained by acidification of EDDANa2 to a pH of 5.50 with nitric acid, while maintaining the temperature of the solution <10° C. The resultant slurry was filtered by means of a Buchner funnel with the vacuum provided by a water aspirator. The filter cake was washed with approximately 7 liters of iced H₂ O. To enhance drying, the cake was then washed with approximately 1 liter of MeOH. The crystals were then placed on 1 inch deep stainless steel trays, dried in a Stokes vacuum dryer, model 338F at 40° C. under a vacuum of 4 mm Hg, for 12 hours. Approximately 2 Kg of a white crystalline powder was recovered. Analysis of this powder showed it to be 98.2% ED2AH₂.

All batches were synthesized on a 0.5 liter scale. 88 g of ED2AH₂ were charged to a 500 ml conical flask and diluted with 180 mls of H₂ O. 50% caustic was used to obtain the sodium salt in the ratio required. This solution was stirred for 30 minutes, and then charged to a 1 liter 5-necked round bottom flask. The conical flask was then washed with 20 mls. of H₂ O, and the washings transferred to the round bottom flask. The round bottom flask was equipped with a magnetic stirring bar, a condenser (ethylene glycol/H₂ O@0° C.), A 0°-250° C. mercury thermometer, and a J-type thermocouple that provided a signal to a Love proportional controller, which maintained the temperature at the desired level were employed. A Glass-Col heating mantle controlled by the Love controller via a Powerstat variable autotransformer was used to heat the contents of the flask. 37% CH₂ O and 100% HCN were pumped at approximately 1 g/minute and 0.50 g/minute, respectively, by an FMI micro metering pump at a setting of 0.5, via 1/8" Teflon tubing to the flask. A 125 ml addition funnel equipped with a Teflon metering valve, and a condenser with the same coolant as described above, was used as the reservoir for the reactants to be pumped. Table 1 shows the results for the experiments conducted up to stage 3 of the reaction. Table 2 shows results for ED3A produced for 9 conditions.

                                      TABLE 1                                      __________________________________________________________________________                                                     %                                                                              EDDA                                                      Moles                                                                              lc %  lc %  lc % to   % Unrxl                                                                             Mass                 Exp Tot wt                                                                             Comments  temp                                                                               l (mins)                                                                            EDDA                                                                               EDDANa2                                                                              ED3ANa3                                                                              3KPNa2                                                                              Produc                                                                              EDDA balance              __________________________________________________________________________                                    220.0 300.00                                                                               260.00                               1-0                                                                               240.75                                                                             2 NaOH/1 EDDA                                                                            50  0.0  0.247                                                                              22.57%                                                                               0.00% 0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               1-1                                                                               238.98                                                                             50° C.                                                                            50  55.0 0.245                                                                              4.36% 0.30% 11.68%                                                                              44.76%                                                                              19.32%                                                                              64.08%                1-2                                                                               234.04        50  102.0                                                                               0.240                                                                              3.03% 0.50% 15.15%                                                                              58.42%                                                                              13.42%                                                                              71.84%                1-3                                                                               228.13        50  144.0                                                                               0.234                                                                              2.13% 0.60% 17.50%                                                                              67.55%                                                                              9.44%                                                                               76.99%                1-4                                                                               221.69        50  199.0                                                                               0.227                                                                              1.51%       19.21%                                                                              72.02%                                                                              6.69%                                                                               78.71%                1-5                                                                               214.52        50  250.0                                                                               0.220                                                                              1.14%       20.54%                                                                              77.00%                                                                              5.05%                                                                               82.05%                1-6                                                                               208.17        50  300.0                                                                               0.214                                                                              0.89% 1.20% 20.90%                                                                              82.25%                                                                              3.94%                                                                               86.19%               final sc                                                                           202.88                                                                      2-0                                                                               240.75                                                                             2 NaOH/1 EDDA                                                                            65  0.0  0.247                                                                              22.57%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               2-1                                                                               240.75                                                                             65° C.                                                                            65  15.0 0.247                                                                              3.84%       13.94%                                                                              52.26%                                                                              17.01%                                                                              69.27%                2-2                                                                               236.21        65  45.0 0.242                                                                              2.58%       17.68%                                                                              66.28%                                                                              11.43%                                                                              77.71%                2-3                                                                               231.19        65  90.0 0.237                                                                              1.49%       20.89%                                                                              78.31%                                                                              6.60%                                                                               84.91%                2-4                                                                               226.19        65  135.0                                                                               0.232                                                                              1.45%       21.64%                                                                              81.12%                                                                              6.42%                                                                               87.55%                2-5                                                                               220.81        65  186.0                                                                               0.227                                                                              1.41%       21.81%                                                                              81.76%                                                                              6.25%                                                                               88.01%                2-6                                                                               214.61        65  230.0                                                                               0.220                                                                              1.36%       21.73%                                                                              81.46%                                                                              6.03%                                                                               87.49%                2-7                                                                               210.35        65  262.0                                                                               0.216                                                                              1.28%       21.74%                                                                              81.50%                                                                              5.67%                                                                               87.17%                2-8                                                                               205.34        65  990.0                                                                               0.211                                                                              1.23%       21.60%                                                                              80.97%                                                                              5.45%                                                                               86.42%               final sc                                                                           197.00        65                                                            3-0                                                                               240.75                                                                             2 NaOH/1 EDDA                                                                            80  0.0  0.247                                                                              22.57%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               3-1                                                                               239.86                                                                             80° C.                                                                            80  10.0 0.246                                                                              4.16%       15.92%                                                                              59.68%                                                                              18.43%                                                                              78.11%                3-2                                                                               235.19        80  35.0 0.241                                                                              3.66%       18.66%                                                                              69.95%                                                                              16.22%                                                                              86.17%                3-3                                                                               229.91        80  75.0 0.236                                                                              3.33%       19.61%                                                                              73.51%                                                                              14.75%                                                                              88.27%                3-4                                                                               223.28        80  136.0                                                                               0.229                                                                              3.04%       19.50%                                                                              73.10%                                                                              13.47%                                                                              86.57%                3-5                                                                               217.66        80  210.0                                                                               0.223                                                                              2.89%       19.77%                                                                              74.11%                                                                              12.80%                                                                              88.92%                3-6                                                                               211.34        80  280.0                                                                               0.217                                                                              2.69%       19.99%                                                                              74.94%                                                                              11.92%                                                                              86.86%               final sc                                                                           205.07        80                                                            4-0                                                                               239.10                                                                             1.9 NaOH/1 EDDA                                                                          50  0.0  0.247                                                                              22.73%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               4-1                                                                               239.10                                                                             50° C.                                                                            50  30.0 0.247                                                                              6.73%       6.34%                                                                               23.60%                                                                              29.61%                                                                              53.22%                4-2                                                                               234.00                                                                             1.0 CH2O  50  70.0 0.242                                                                              5.00%       10.24%                                                                              38.12%                                                                              22.00%                                                                              60.13%                4-3                                                                               228.81        50  115.0                                                                               0.236                                                                              4.18%       13.58%                                                                              50.56%                                                                              18.39%                                                                              68.95%                4-4                                                                               223.25        50  165.0                                                                               0.231                                                                              2.68%       16.40%                                                                              61.06%                                                                              11.79%                                                                              72.85%                4-5                                                                               217.35        50  200.0                                                                               0.225                                                                              2.16%       17.99%                                                                              66.98%                                                                              9.50%                                                                               76.48%                4-6                                                                               212.72        50  250.0                                                                               0.220                                                                              1.52%       19.66%                                                                              73.20%                                                                              6.69%                                                                               79.89%                4-7                                                                               208.46        50  285.0                                                                               0.215                                                                              1.14%       20.75%                                                                              77.26%                                                                              5.02%                                                                               82.27%                4-8                                                                               192.50        50  1280.0                                                                              0.199                                                                              0.13% 1.10% 23.50%                                                                              91.04%                                                                              0.57%                                                                               91.62%               final so                                                                           138.00        boiled   0.201                                                                              0.13%       32.75%                                                                              86.36%                                                                              0.41%                                                                               86.77%                5-0                                                                               241.10                                                                             2.1 NaOH/1 EDDA                                                                          50  0    0.247                                                                              22.54%                                                                               0.00% 0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               5-1                                                                               241.10                                                                             50° C.                                                                            50  40.0 0.247                                                                              5.58% 0.10% 9.35%                                                                               35.43%                                                                              24.76%                                                                              60.19%                5-2                                                                               236.01                                                                             1.05 CH2O 50  90.0 0.242                                                                              3.85% 0.20% 14.31%                                                                              54.37%                                                                              17.08%                                                                              71.46%                5-3                                                                               231.32        50  138.0                                                                               0.237                                                                              2.75% 0.50% 17.20%                                                                              66.20%                                                                              12.20%                                                                              78.40%                5-4                                                                               225.41        50  186.0                                                                               0.231                                                                              2.15% 0.80% 18.60%                                                                              72.43%                                                                              9.54%                                                                               81.97%                5-5                                                                               220.92        50  228.0                                                                               0.226                                                                              1.71% 1.00% 19.41%                                                                              76.12%                                                                              7.59%                                                                               83.71%                5-6                                                                               216.39        50  260.0                                                                               0.222                                                                              1.49% 1.30% 19.85%                                                                              78.75%                                                                              6.61%                                                                               85.36%                5-7                                                                               211.83        50  1350.0                                                                              0.217                                                                              0.66% 3.40% 16.01%                                                                              71.17%                                                                              2.93%                                                                               74.10%               final so                                                                           170.21        boiled   0.220                                                                              0.92% 5.10% 23.10%                                                                              82.02%                                                                              3.24%                                                                               85.26%                5-0                                                                               239.10                                                                             1.9 NaOH/1 EDDA                                                                          80  0.0  0.247                                                                              22.73%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               5-1                                                                               239.10                                                                             80° C.                                                                            80  15.0 0.247                                                                              3.61%       17.05%                                                                              63.48%                                                                              15.88%                                                                              79.36%                5-2                                                                               233.80                                                                             1.05 CH2O 80  45.0 0.242                                                                              3.01%       18.70%                                                                              69.62%                                                                              13.24%                                                                              82.87%                5-3                                                                               229.09        80  90.0 0.237                                                                              2.61%       19.78%                                                                              73.64%                                                                              11.48%                                                                              85.13%                5-4                                                                               222.74        80  145.0                                                                               0.230                                                                              2.26%       20.36%                                                                              75.80%                                                                              9.94%                                                                               85.75%                5-5                                                                               217.86        80  189.0                                                                               0.225                                                                              1.32%       20.11%                                                                              74.87%                                                                              5.81%                                                                               80.68%                5-6                                                                               213.47        80  240.0                                                                               0.221                                                                              1.60%       18.26%                                                                              67.98%                                                                              7.04%                                                                               75.02%                5-7                                                                               208.33        80  285.0                                                                               0.215                                                                              1.66%       21.35%                                                                              79.49%                                                                              7.30%                                                                               86.79%                5-8                                                                               203.47        80  1282.0                                                                              0.210                                                                              0.40% 0.10% 20.90%                                                                              78.14%                                                                              1.76%                                                                               79.90%                5-9                                                                               157.60        boiled   0.213                                                                              0.60% 0.50% 27.75%                                                                              80.30%                                                                              2.02%                                                                               82.32%                6-0                                                                               241.10                                                                             2.1 NaOH/1 EDDA                                                                          80  0.0  0.247                                                                              22.54%                                                                               0.00% 0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               6-1                                                                               241.10                                                                             80° C.                                                                            80  20.0 0.247                                                                              3.72% 1.00% 18.17%                                                                              71.47%                                                                              16.51%                                                                              87.97%                6-2                                                                               235.20                                                                             1.00 CH2O 80  74.0 0.241                                                                              3.44% 1.00% 19.09%                                                                              74.92%                                                                              15.26%                                                                              90.19%                6-3                                                                               229.95        80  110.0                                                                               0.236                                                                              3.47% 1.00% 19.15%                                                                              75.15%                                                                              15.40%                                                                              90.54%                6-4                                                                               225.49        80  155.0                                                                               0.231                                                                              3.37% 1.00% 19.44%                                                                              76.24%                                                                              14.95%                                                                              91.19%                6-5                                                                               220.51        80  200.0                                                                               0.226                                                                              3.14% 1.00% 19.06%                                                                              74.81%                                                                              13.93%                                                                              88.74%                6-6                                                                               215.06        80  238.0                                                                               0.220                                                                              3.15% 1.00% 19.20%                                                                              75.34%                                                                              13.98%                                                                              89.31%                6-7                                                                               210.36        80  286.0                                                                               0.216                                                                              3.06% 1.00% 18.81%                                                                              73.87%                                                                              13.58%                                                                              87.45%                6-8                                                                               204.01        80  320.0                                                                               0.209                                                                              3.08% 1.00% 19.19%                                                                              75.30%                                                                              13.67%                                                                              88.96%                 6-9                                                                              198.58        80  1286.0                                                                              0.203                                                                              2.30% 1.70% 19.39%                                                                              78.33%                                                                              10.20%                                                                              88.53%                6-10                                                                              145.33        boiled   0.206                                                                              2.49% 1.80% 21.94%                                                                              63.79%                                                                              7.99%                                                                               71.78%                7-0                                                                               239.10                                                                             1.9 NaOH/1 EDDA                                                                          80  0.0  0.247                                                                              22.73%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               7-1                                                                               239.10                                                                             80° C.                                                                            80  26.0 0.247                                                                              3.32%       16.83%                                                                              62.66%                                                                              14.61%                                                                              77.27%                7-2                                                                               233.84                                                                             1.00 CH2O 80  71.0 0.242                                                                              2.87%       19.69%                                                                              73.31%                                                                              12.63%                                                                              85.94%                7-3                                                                               228.66        80  119.0                                                                               0.236                                                                              2.42%       19.79%                                                                              73.68%                                                                              10.65%                                                                              84.33%                7-4                                                                               223.62        80  160.0                                                                               0.231                                                                              2.31%       20.21%                                                                              75.24%                                                                              10.16%                                                                              85.41%                7-5                                                                               218.59        80  208.0                                                                               0.226                                                                              1.99%       20.36%                                                                              75.80%                                                                              8.76%                                                                               84.56%                7-6                                                                               213.40        80  260.0                                                                               0.220                                                                              1.88%       20.24%                                                                              75.36%                                                                              8.27%                                                                               83.63%                7-7                                                                               207.57        80  1291.0                                                                              0.214                                                                              0.51%       19.85%                                                                              73.90%                                                                              2.24%                                                                               76.15%                7-8                                                                               127.47        boiled   0.217                                                                              0.94% 1.80% 30.58%                                                                              72.60%                                                                              2.51%                                                                               75.11%                8-0                                                                               239.10                                                                             1.9 NaOH/1 EDDA                                                                          50  0.0  0.247                                                                              22.73%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               8-1                                                                               239.10                                                                             50° C.                                                                            50  35.0 0.247                                                                              1.89%       20.44%                                                                              76.10%                                                                              8.32%                                                                               84.42%                8-2                                                                               233.30                                                                             1.05 CH2O 50  117.0                                                                               0.241                                                                              1.29%       22.46%                                                                              83.62%                                                                              5.68%                                                                               89.30%                8-3                                                                               228.81        50  160.0                                                                               0.236                                                                              1.07%       23.18%                                                                              86.30%                                                                              4.71%                                                                               91.01%                8-4                                                                               223.96        50  210.0                                                                               0.231                                                                              0.82%       23.29%                                                                              86.71%                                                                              3.61%                                                                               90.32%                8-5                                                                               218.87        50  297.0                                                                               0.226                                                                              0.56%       24.16%                                                                              89.95%                                                                              2.46%                                                                               92.42%                8-6                                                                               199.40        50  1261.0                                                                              0.206                                                                              0.24%       24.96%                                                                              92.93%                                                                              1.06%                                                                               93.99%                8-7                                                                               141.00        boiled   0.206                                                                              0.27% 1.10% 35.02%                                                                              94.71%                                                                              0.84%                                                                               95.55%                9-0                                                                               241.10                                                                             2.1 NaOH/1 EDDA                                                                          50  0.0  0.247                                                                              22.54%      0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%               9-1                                                                               241.10                                                                             50° C.                                                                            50  30.0 0.247           9.07%                                                                               34.05%                                                                              0.00%                                                                               34.05%                9-2                                                                               235.44                                                                             1.00 CH2O 50  112.0                                                                               0.241                                                                              2.71% 0.60% 16.04%                                                                              62.17%                                                                              12.02%                                                                              74.19%                9-3                                                                               230.22        50  168.0                                                                               0.236                                                                              2.10% 0.70% 18.36%                                                                              71.21%                                                                              9.32%                                                                               80.52%                9-4                                                                               225.60        50  211.0                                                                               0.231                                                                              1.55% 1.10% 19.28%                                                                              75.96%                                                                              6.88%                                                                               82.84%                9-5                                                                               220.60        50  250.0                                                                               0.226                                                                              1.02% 1.20% 20.77%                                                                              81.88%                                                                              4.53%                                                                               86.41%                9-6                                                                               214.87        50  1380.0                                                                              0.220                                                                              0.89% 3.30% 20.16%                                                                              86.42%                                                                              3.95%                                                                               90.37%                9-7                                                                               112.00        boiled   0.223                                                                              1.51% 9.60% 34.28%                                                                              82.36%                                                                              3.45%                                                                               85.81%               10-0                                                                               241.10                                                                             2.1 NaOH/1 EDDA                                                                          80  0.0  0.247                                                                              22.54%                                                                               0     0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%              10-1                                                                               241.10                                                                             80° C.                                                                            80  30.0 0.247                                                                              3.82% 0.70% 19.28%                                                                              74.66%                                                                              16.95%                                                                              91.61%               10-2                                                                               236.36                                                                             1.05 CH2O 80  88.0 0.242                                                                              3.42% 0.60% 19.50%                                                                              75.16%                                                                              15.17%                                                                              90.33%               10-3                                                                               231.84        80  133.0                                                                               0.238                                                                              3.32% 0.80% 20.04%                                                                              77.84%                                                                              14.73%                                                                              92.57%               10-4                                                                               226.84        80  196.0                                                                               0.232                                                                              2.99% 0.50% 17.77%                                                                              68.34%                                                                              13.27%                                                                              81.61%               10-5                                                                               221.45        80  240.0                                                                               0.227                                                                              3.21% 0.70% 20.42%                                                                              78.94%                                                                              14.24%                                                                              93.18%               10-6                                                                               216.41        80  293.0                                                                               0.222                                                                              3.09% 0.01% 19.99%                                                                              75.07%                                                                              13.71%                                                                              88.78%               10-7                                                                               210.56        80  1290.0                                                                              0.216                                                                              2.16% 1.00% 19.30%                                                                              75.71%                                                                              9.58%                                                                               85.30%               10-8                                                                               138.64        boiled   0.218                                                                              3.22% 2.50% 28.68%                                                                              75.34%                                                                              9.29%                                                                               84.63%               11-0                                                                               263.10                                                                             3.1 NaOH/1 EDDA                                                                          35  0.0  0.247                                                                              20.65%                                                                               0.00% 0    0.00%                                                                               100.00%                                                                             100.00%              11-1                                                                               263.10                                                                             35° C.                                                                            35  35.0 0.247                                                                              8.47%       2.37%                                                                               9.71%                                                                               41.01%                                                                              50.72%               11-2                                                                               258.10                                                                             1.00 CH2O 35  72.0 0.242           4.89%                                                                               20.03%                                                                              0.00%                                                                               20.03%               11-3                                                                               252.90        35  143.0                                                                               0.237                                                                              7.21%       6.40%                                                                               26.22%                                                                              34.91%                                                                              61.13%               11-4                                                                               247.40        35  182.0                                                                               0.232                                                                              7.20% 0.60% 6.81%                                                                               30.03%                                                                              34.86%                                                                              64.89%               11-5                                                                               242.74        35  221.0                                                                               0.228                                                                              6.89% 0.70% 8.25%                                                                               36.28%                                                                              33.36%                                                                              69.64%               11-6                                                                               238.43        35  257.0                                                                               0.224                                                                              6.60% 1.10% 9.49%                                                                               42.78%                                                                              31.96%                                                                              74.74%               11-7                                                                               233.63        35  1360.0                                                                              0.219                                                                              2.88% 12.00%                                                                               9.08%                                                                               79.81%                                                                              13.94%                                                                              93.75%               11-8                                                                               140.00        boiled   0.222                                                                              4.22% 34.30%                                                                               5.27%                                                                               84.89%                                                                              12.10%                                                                              96.98%               12-0                                                                               263.10                                                                             3.1 NaOH/1 EDDA                                                                          50  0.0  0.247                                                                              20.65%                                                                               0.00% 0.00%                                                                               0.00%                                                                               100.00%                                                                             100.00%              12-1                                                                               263.10                                                                             50° C.                                                                            50  13.0 0.247                                                                              6.20% 0.40% 12.39%                                                                              52.18%                                                                              30.02%                                                                              82.20%               12-2                                                                               257.27                                                                             1.00 CH2O 50  54.0 0.242                                                                              6.04% 1.80% 11.35%                                                                              52.89%                                                                              29.24%                                                                              82.13%               12-3                                                                               251.81        50  98.0 0.236                                                                              4.84% 3.50% 12.49%                                                                              63.60%                                                                              23.43%                                                                              87.03%               12-4                                                                               247.54        50  147.0                                                                               0.232                                                                              4.22% 4.90% 12.90%                                                                              70.25%                                                                              20.43%                                                                              90.68%               12-5                                                                               243.10        50  1237.0                                                                              0.228                                                                              3.47% 15.90%                                                                               8.07%                                                                               89.52%                                                                              16.80%                                                                              106.32%              12-6                                                                               138.80        boiled   0.231                                                                              5.50% 40.00%                                                                               5.45%                                                                               92.71%                                                                              15.02%                                                                              107.73%              13-0                                                                               271.10                                                                             3.5 NaOH/1 EDDA                                                                          35  0.0  0.247                                                                              20.04%                                                                               0.00% 0    0.00%                                                                               100.00%                                                                             100.00%              13-1                                                                               271.10                                                                             35° C.                                                                            35  10.0 0.247                                                                              9.60%       4.02%                                                                               16.97%                                                                              47.89%                                                                              64.86%               13-2                                                                               265.99                                                                             1.00 CH2O 35  47.0 0.242                                                                              7.82%       8.07%                                                                               34.07%                                                                              39.01%                                                                              73.08%               13-3                                                                               261.37        35  90.0 0.238                                                                              7.31%       9.19%                                                                               38.79%                                                                              36.47%                                                                              75.26%               13-4                                                                               256.60        35  130.0                                                                               0.234                                                                              6.70% 0.80% 9.46%                                                                               42.86%                                                                              33.43%                                                                              76.29%               13-5                                                                               252.16        35  186.0                                                                               0.230                                                                              6.35% 0.80% 10.36%                                                                              46.66%                                                                              31.68%                                                                              78.34%               13-6                                                                               246.06        35  230.0                                                                               0.224                                                                              6.12% 1.40% 10.54%                                                                              49.62%                                                                              30.53%                                                                              80.15%               13-7                                                                               241.06        35  308.0                                                                               0.220                                                                              6.16% 2.30% 10.43%                                                                              52.44%                                                                              30.73%                                                                              83.18%               13-8                                                                               235.25        35  1320.0                                                                              0.214                                                                              2.52% 13.90%                                                                               6.98%                                                                               80.32%                                                                              12.57%                                                                              92.89%               burned                                                                         14-0                                                                               443.96                                                                             1.8 NaOH/1 EDDA                                                                          65  13.0 0.491           5.38%                                                                               18.71%                                                                              0.00%                                                                               18.71%               14-1                                                                               442.63                                                                             65° C.                                                                            65  49.0 0.490           10.48%                                                                              36.45%                                                                              0.00%                                                                               36.45%               14-2                                                                               440.98                                                                             1.00 CH2O 65  107.0                                                                               0.488           16.17%                                                                              56.23%                                                                              0.00%                                                                               56.23%               14-3                                                                               439.19        65  1063.0                                                                              0.486           21.12%                                                                              73.45%                                                                              0.00%                                                                               73.45%               15-0                                                                               448.82                                                                             1.9 NaOH/1 EDDA                                                                          50  25.0 0.491           2.05%                                                                               7.21%                                                                               0.00%                                                                               7.21%                15-1                                                                               447.52                                                                             50° C.                                                                            50  85.0 0.490           7.06%                                                                               24.82%                                                                              0.00%                                                                               24.82%               15-2                                                                               446.05                                                                             1.05 CH2O 50  122.0                                                                               0.488           9.97%                                                                               35.05%                                                                              0.00%                                                                               35.05%               15-3                                                                               444.25        50  173.0                                                                               0.486           13.01%                                                                              45.74%                                                                              0.00%                                                                               45.74%               15-4                                                                               443.14        50  1238.0                                                                              0.485           25.10%                                                                              88.25%                                                                              0.00%                                                                               88.25%               15-5                                                                               441.95        50       0.485           25.52%                                                                              89.48%                                                                              0.00%                                                                               89.48%               16-0                                                                               450.68                                                                             1.9 NaOH/1 EDDA                                                                          65  10.0 0.491           6.67%                                                                               23.55%                                                                              0.00%                                                                               23.55%               16-1                                                                               449.03                                                                             65° C.                                                                            65  41.0 0.489           12.47%                                                                              44.02%                                                                              0.00%                                                                               44.02%               16-2                                                                               447.46                                                                             1.00 CH2O 65  82.0 0.487           17.76%                                                                              62.70%                                                                              0.00%                                                                               62.70%               16-3                                                                               446.18        65  125.0                                                                               0.486           20.24%                                                                              71.45%                                                                              0.00%                                                                               71.45%               16-4                                                                               444.85        65  1080.0                                                                              0.486           24.22%                                                                              85.25%                                                                              0.00%                                                                               85.25%               17-0                                                                               450.70                                                                             1.9 NaOH/1 EDDA                                                                          75  17.0 0.491           14.87%                                                                              52.50%                                                                              0.00%                                                                               52.50%               17-1                                                                               449.45                                                                             75° C.                                                                            75  48.0 0.490           20.66%                                                                              72.94%                                                                              0.00%                                                                               72.94%               17-2                                                                               448.35                                                                             1.05 CH2O 75  98.0 0.488           24.26%                                                                              85.65%                                                                              0.00%                                                                               85.65%               17-3                                                                               447.08        75  239.0                                                                               0.487           24.97%                                                                              88.16%                                                                              0.00%                                                                               88.16%               17-4                                                                               445.66        75  1233.0                                                                              0.486           26.24%                                                                              92.64%                                                                              0.00%                                                                               92.64%               17-5                                                                               407.20        boil                                                                               boil 0.486           26.41%                                                                              85.19%                                                                              0.00%                                                                               85.19%               18-0                                                                               450.70                                                                             1.9 NaOH/1 EDDA                                                                          50° C.                                                                      10.0 0.491           1.36%                                                                               4.80%                                                                               0.00%                                                                               4.80%                18-1                                                                               449.36                                                                             50° C.                                                                            50° C.                                                                      88.0 0.490           7.60%                                                                               25.63%                                                                              0.00%                                                                               26.83%               18-2                                                                               447.82                                                                             1.00 CH2O 50° C.                                                                      1365.0                                                                              0.488           24.84%                                                                              85.98%                                                                              0.00%                                                                               85.93%               18-3                                                                               392.30        boil                                                                               boil 0.488           27.84%                                                                              86.10%                                                                              0.00%                                                                               86.10%               19-0                                                                               446.70                                                                             1.8 NaOH/1 EDDA                                                                          50° C.                                                                      41.0 0.491           2.59%                                                                               9.06%                                                                               0.00%                                                                               9.06%                19-1                                                                               445.33                                                                             50° C.                                                                            50° C.                                                                      120.0                                                                               0.489           8.63%                                                                               30.20%                                                                              0.00%                                                                               30.20%               19-2                                                                               443.88                                                                             1.00 CH2O 50° C.                                                                      164.0                                                                               0.488           11.36%                                                                              39.75%                                                                              0.00%                                                                               39.75%               19-3                                                                               442.48        50° C.                                                                      1400.0                                                                              0.486           24.71%                                                                              86.46%                                                                              0.00%                                                                               86.46%               19-4                                                                               343.20        boil                                                                               boil 0.486           31.79%                                                                              86.28%                                                                              0.00%                                                                               86.28%               20-0                                                                               446.07                                                                             1.8 NaOH/1 EDDA                                                                          50° C.                                                                      60.0 0.491           3.35%                                                                               11.71%                                                                              0.00%                                                                               11.71%               20-1                                                                               444.76                                                                             50° C.                                                                            50° C.                                                                      210.0                                                                               0.490           13.30%                                                                              46.47%                                                                              0.00%                                                                               46.47%               20-2                                                                               442.90                                                                             1.05 CH2O 50° C.                                                                      300.0                                                                               0.488           16.72%                                                                              58.42%                                                                              0.00%                                                                               58.42%               20-3                                                                               441.42        50° C.                                                                      1250.0                                                                              0.486           24.46%                                                                              85.47%                                                                              0.00%                                                                               85.47%               20-4                                                                               353.40        boil                                                                               boil 0.486           30.81%                                                                              86.19%                                                                              0.00%                                                                               86.19%               21-0                                                                               446.70                                                                             1.8 NaOH/1 EDDA                                                                          65° C.                                                                      16.0 0.491           7.03%                                                                               24.60%                                                                              0.00%                                                                               24.60%               21-1                                                                               444.89                                                                             65° C.                                                                            65°  C.                                                                     85.0 0.489           17.26%                                                                              60.40%                                                                              0.00%                                                                               60.40%               21-2                                                                               443.09                                                                             1.05 CH2O 65° C.                                                                      175.0                                                                               0.487           22.05%                                                                              77.16%                                                                              0.00%                                                                               77.16%               21-3                                                                               441.24        65° C.                                                                      253.0                                                                               0.485           23.83%                                                                              83.38%                                                                              0.00%                                                                               83.38%               21-4                                                                               439.56        65° C.                                                                      1240.0                                                                              0.483           24.40%                                                                              85.38%                                                                              0.00%                                                                               85.38%               21-5                                                                               380.00        boil                                                                               boil 0.483           24.96%                                                                              75.50%                                                                              0.00%                                                                               75.50%               22-0                                                                               446.70                                                                             1.8 NaOH/1 EDDA                                                                          65° C.                                                                      25.0 0.491           9.99%                                                                               34.96%                                                                              0.00%                                                                               34.96%               22-1                                                                               444.33                                                                             65° C.                                                                            65° C.                                                                      110.0                                                                               0.488           19.71%                                                                              68.97%                                                                              0.00%                                                                               68.97%               22-2                                                                               442.74                                                                             1.00 CH2O 65° C.                                                                      165.0                                                                               0.487           21.34%                                                                              74.67%                                                                              0.00%                                                                               74.67%               22-3                                                                               441.04        65° C.                                                                      208.0                                                                               0.485           21.40%                                                                              74.88%                                                                              0.00%                                                                               74.88%               22-4                                                                               439.65        65° C.                                                                      1292.0                                                                              0.483           23.72%                                                                              83.00%                                                                              0.00%                                                                               83.00%               22-5                                                                               394.70        boil                                                                               boil 0.483           25.87%                                                                              81.27%                                                                              0.00%                                                                               81.27%               23-0                                                                               450.70                                                                             1.9 NaOH/1 EDDA                                                                          65° C.                                                                      33.0 0.491           11.14%                                                                              39.33%                                                                              0.00%                                                                               39.33%               23-1                                                                               448.95                                                                             65° C.                                                                            65° C.                                                                      92.0 0.489           18.65%                                                                              65.84%                                                                              0.00%                                                                               65.84%               23-2                                                                               447.21                                                                             1.05 CH2O 65° C.                                                                      148.0                                                                               0.487           21.69%                                                                              76.58%                                                                              0.00%                                                                               76.58%               23-3                                                                               445.41        65° C.                                                                      230.0                                                                               0.485           23.32%                                                                              82.33%                                                                              0.00%                                                                               82.33%               23-4                                                                               443.77        65° C.                                                                      1276.0                                                                              0.483           24.79%                                                                              87.52%                                                                              0.00%                                                                               87.52%               23-5                                                                               408.62        boil                                                                               boil 0.483           26.43%                                                                              85.92%                                                                              0.00%                                                                               85.92%               __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________                                                        %                                                                              3KPNA2                                                % 3KPNa2    moles after                                                                          % conversion                                                                          after                       Exp                                                                               Temp °C.                                                                     M CH2O                                                                              EDDA:NaOH                                                                              final wt                                                                            recyclized                                                                           moles 3KP                                                                            sampling                                                                             recyclized                                                                            stage                       __________________________________________________________________________                                                        1                           1  50.00                                                                               1.05 1.90    373.40                                                                              31.39%                                                                               0.45  0.48  92.99% 89.48%                      2  65.00                                                                               1.00 1.90    364.00                                                                              31.91%                                                                               0.45  0.49  91.91% 85.25%                      3  75.00                                                                               1.05 1.90    376.40                                                                              29.53%                                                                               0.43  0.49  88.04% 85.19%                      4  50.00                                                                               1.00 1.90    372.80                                                                              31.77%                                                                               0.46  0.49  93.37% 86.10%                      5  50.00                                                                               1.00 1.80    370.30                                                                              32.10%                                                                               0.46  0.49  94.00% 86.28%                      6  50.00                                                                               1.05 1.80    388.95                                                                              30.89%                                                                               0.46  0.49  94.41% 86.19%                      7  65.00                                                                               1.05 1.80    393.60                                                                              29.71%                                                                               0.45  0.48  93.07% 85.38%                      8  65.00                                                                               1.00 1.80    415.60                                                                              26.86%                                                                               0.43  0.48  88.82% 81.27%                      9  65.00                                                                               1.05 1.90    417.70                                                                              29.82%                                                                               0.48  0.48  99.08% 85.92%                      __________________________________________________________________________                           % difference                                                                          % unopened                                                                            % ED3ANa3                                                                             % conversion                                                                          % total conv                                    Exp                                                                               at 1-recycle                                                                          3KPNa2 by titr                                                                               to ED3ANa3                                                                            on ED3ANa3                   __________________________________________________________________________                        1  -3.51% 2.05%  36.00% 91.28% 95.74%                                          2  -6.85% 1.88%  38.32% 94.89% 98.23%                                          3  -2.85% 2.09%  36.55% 93.40% 97.87%                                          4  -7.27% 2.17%  38.16% 96.58% 100.67%                                         5  -7.72% 2.28%  37.50% 94.27% 98.99%                                          6  -8.22% 2.69%  35.39% 93.45% 99.10%                                          7  -7.69% 2.85%  34.13% 91.20% 98.76%                                          8  -7.55% 3.08%  32.54% 91.81% 100.56%                                         9  -13.16%                                                                               2.43%  32.10% 91.03% 97.70%                       __________________________________________________________________________

The data demonstrate that both mass balances and conversions to product are excellent. ED3A was measured by copper(II) salt titration, and 3KP was measured by high pressure liquid chromatography (HPLC). The final column in the Table 1 shows the mass balances for stage 3 of the reaction. The 9th column in Table 2 shows the percent conversion to product based on recyclization. Recyclization was achieved by acidifying a sample of the reaction mass with HCl to a pH of 2.0. These samples were then allowed to stand in an oven at 40° C. overnight an then on a bench at room temperature for 2 days prior to analysis. This technique was employed to verify the titration results, ensuring that all product was recyclized to 3KPH₂. Mass balances are not as good as those that were titrated, and this may be attributed to HPLC error and dilution error, etc.

In the second embodiment of the instant invention, ED2AH₂ was slurried with water. 37% CH₂ O and HCN were added in the same manner as previous runs. No salts were present. It was found that the reaction proceeded as described in the second embodiment of the invention. The ED2AH₂, water and formaldehyde reacted to give the hydroxymethyl derivative of the lactam, which in turn reacted with HCN to give the cyclized mono-nitrile-monoacid. This solution was allowed to react overnight at 65° C. and one large peak was found on the chromatograms upon analysis by HPLC, which was later confirmed to be 1-cyanomethyl-4-carboxymethyl-3-ketopiperazine. The batch was then split in two. When the solution was cooled to <50° C., crystals precipitated which were subsequently isolated in approximately 70% yield. The other half of the batch was hydrolyzed with caustic (2:1 mole ratio, NaOH: EDDA), NH₃ was liberated, and it was found that 3KPNa₂ was the only product. This suggests the material was the mono-nitrile-diacid. Final confirmation of this structure was successfully conducted by C¹³ NMR. No attempts were made to enhance the recovery of the crystals, which is easily performed by concentration, pH adjustment, further cooling, etc.

A further example was carried out using glycolonitrile, as follows. 17.6 grams of EDDAH₂ were slurried in water. The solution was heated to about 70° C. and 5.7 grams of glycolonitrile were added. Three samples were taken approximately 20 minutes apart. Analysis of these samples by HPLC showed a progressive increase in mononitrile monoacid, however it was not quantified. 

What is claimed is:
 1. A process for the preparation of salts of ethylenediamine triacetic acid, comprising:a. reacting formaldehyde with ethylenediamine diacetic acid in an aqueous medium; b. reacting the reaction product of step a with a cyanide source; c. hydrolyzing the resulting reaction product; and d. reacting the hydrolyzed product with an alkali metal or alkaline earth metal hydroxide to form the alkali metal or alkaline earth metal salt of ethylenediamine triacetic acid.
 2. The process of claim 1 wherein said aqueous medium is acidified with an acid having a pK_(a) less than or equal to
 3. 3. The process of claim 2 wherein said acidification results in the formation of N-carboxymethyl-3-ketopiperazine.
 4. The process of claim 2, wherein said acidification is carried out prior to step b.
 5. The process of claim 2, wherein said acidification is carried out during step b.
 6. The process of claim 2, wherein said acidification is carried out after step b.
 7. The process of claim 1, wherein said cyanide source is selected from the group consisting of hydrogen cyanide and alkali metal cyanide.
 8. The process of claim 1, wherein the reaction of formaldehyde and ethylenediamine diacetic acid is conducted at a temperature from about 0° to about 65 ° C.
 9. The process of claim 1, wherein the reaction of formaldehyde and ethylenediamine diacetic acid is conducted at a temperature from about 15° to about 65° C.
 10. The process of claim 1, wherein the reaction of step b is conducted at a temperature from about 0° to about 65° C.
 11. The process of claim 1 wherein the reaction of step b is conducted at a temperature from about 15° to about 65° C.
 12. The process of claim 1, wherein the solution in step d is heated by ramping to boil over a period of about thirty minutes to about six hours.
 13. The process of claim 1, wherein said formaldehyde is added in a slight molar excess.
 14. The process of claim 1, wherein said cyanide source is added in a slight molar excess.
 15. The process of claim 1, wherein said alkali metal or alkaline earth metal hydroxide is added to said hydrolyzed product in at least a 1 molar excess.
 16. The process of claim 1, further comprising cooling the reaction product of step b and isolating 1-cyanomethyl-4-carboxymethyl-3-ketopiperazine. 